The overall goal of this proposal is to characterize the mechanisms of signal integration between ITAM-containing receptor complexes and cytokine receptors that signal through the Jak-STAT pathways. ITAM-containing receptors play prominent role in all aspects of leukocyte function. Their activation usually requires tyrosine (Y) phosphorylation and therefore, depends on a 'priming signal'delivered from a Y-kinase, generally assumed to be the member of a Src family kinases (SFK). Receptor 'priming'is followed by a recruitment and activation of SH2 containing Y-kinases: Syk-72 or ZAP-70, which initiate several downstream signaling pathways. However, different ITAM-containing receptors respond to a broad variety of ligands and produce distinct biological outcomes, raising the question as to how specificity of cellular response is achieved if the same receptor uses the same signaling module under all circumstances. Emerging data, including those from our group, suggest a role for cytokine receptors and Jak kinases in priming/modulating the signals emanating from ITAM-containing receptors. Based on these findings, we propose to investigate the hypothesis that Jak kinases activated by appropriate cytokine receptors are involved in Y-phosphorylation of ITAM and ITAM-like receptors/adaptors, thereby coupling the recognition of two distinct types of signals: ligands recognized by ITAM-containing receptors and cytokines. We further hypothesize that this type of signal integration provides specificity of cellular responses, and makes them conditional upon the appropriate context defined by the cytokines produced in distinct physiological settings. We expect that the results of our investigation will provide a new model of signaling by the two major families of receptors in leukocytes: cytokine receptors and ITAM-containing immunoreceptors. PUBLIC HEALTH RELEVANCE: Leukocyte functions are regulated by two major families of receptors: the ITAM-containing receptors and cytokine receptors. We propose to characterize the new mechanism of regulation of signaling by the two receptor families that would explain the context dependent function of leukocytes. The proposed studies will reveal new possibilities for therapeutic interventions for immune and inflammatory disorders.